Disturbances in Calcium Homeostasis Promotes Skeletal Muscle Atrophy: Lessons From Ventilator-Induced Diaphragm Wasting

Abstract

Mechanical ventilation (MV) is often a life-saving intervention for patients in respiratory failure. Unfortunately, a common and undesired consequence of prolonged MV is the development of diaphragmatic atrophy and contractile dysfunction. This MV-induced diaphragmatic weakness is commonly labeled "ventilator-induced diaphragm dysfunction" (VIDD). VIDD is an important clinical problem because diaphragmatic weakness is a major risk factor for the failure to wean patients from MV; this inability to remove patients from ventilator support results in prolonged hospitalization and increased morbidity and mortality. Although several processes contribute to the development of VIDD, it is clear that oxidative stress leading to the rapid activation of proteases is a primary contributor. While all major proteolytic systems likely contribute to VIDD, emerging evidence reveals that activation of the calcium-activated protease calpain plays a required role. This review highlights the signaling pathways leading to VIDD with a focus on the cellular events that promote increased cytosolic calcium levels and the subsequent activation of calpain within diaphragm muscle fibers. In particular, we discuss the emerging evidence that increased mitochondrial production of reactive oxygen species promotes oxidation of the ryanodine receptor/calcium release channel, resulting in calcium release from the sarcoplasmic reticulum, accelerated proteolysis, and VIDD. We conclude with a discussion of important and unanswered questions associated with disturbances in calcium homeostasis in diaphragm muscle fibers during prolonged MV.

Keywords: calpain; muscle atrophy; oxidative stress; proteolysis; reactive oxygen species; ryanodine receptors.

FIGURE 1

Illustration of calcium (Ca²⁺) regulation at the sarcolemma. Dihydropyridine receptors (DHPR) mediate Ca²⁺ release from the sarcoplasmic reticulum into the cytosol. Calstabin-1 is bound to RyR1 and stabilizes this complex to aid in maintaining a closed channel. Ca²⁺ is pumped back into the sarcoplasmic reticulum via sarcoplasmic reticulum Ca²⁺-ATPase (SERCA). Ca²⁺ enters from the extracellular space via voltage-gated channels, store-operated channels (SOC), and receptor operated channels (ROC). Ca²⁺ is excreted from the cytosol via plasma membrane Ca²⁺ ATPases (PMCA) and Na⁺/Ca²⁺ exchanger (NCX). Levels of cytosolic free Ca²⁺ are also regulated by Ca²⁺ binding proteins such as Troponin-C, parvalbumin, and calmodulin.

FIGURE 2

Illustration of mitochondrial calcium transport. Mitochondrial associated membranes (MAMs) result in microdomains of high Ca²⁺ levels that facilitate Ca²⁺ entry through the outer mitochondrial membrane via voltage dependent anion channel (VDAC). Ca²⁺ crosses the inner mitochondrial membrane via the mitochondrial uniporter (MCU), which then stimulates respiration via increases in citric acid cycle enzymes. Ca²⁺ is extruded from the mitochondria via Na⁺/Ca²⁺ exchanger (NCX) and H⁺/Ca²⁺ exchanger (HCX) in the inner membrane and the outer membrane via the mitochondrial permeability transition pore (mPTP).

FIGURE 3

Mechanical ventilation causes Ca²⁺ disruptions that lead to increased proteolysis. ROS production from mitochondria, along with increased protein kinase A (PKA) activity, modify ryanodine receptors (RyR1) leading to the disassociation of calstabin-1. Disassociation of calstabin-1 from RyR1 leads to Ca²⁺ leak, activation of calpains, and increased proteolysis that contributes to VIDD.